The invention relates to a pharmaceutical composition which contains cefuroximaxetil and ensures improved release of the active ingredient from dosage forms. The invention also relates to a stable crystalline modification of cefuroximaxetil.
Cefuroximaxetil (ATC code J01DA45) is broad spectrum antibiotic of the cephalosporin class which is conventionally administered orally. Administration of cefuroximaxetil is indicated in infections of the airways, of the urogenital tract and in otorhinolaryngeal infections. It may also be administered in soft tissue infections and infections of the bones and joints (c.f. L. J. Scott et al., Drugs 2001, 61, 1455-1500).
Cefuroximaxetil is the 1-acetoxyethyl ester of cefuroxime, i.e. of (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (c.f. U.S. Pat. No. 3,974,153 and U.S. Pat. No. 4,267,320; ATC code J01DA06). Where approved for pharmaceutical use, cefuroximaxetil conventionally comprises a mixture of two diastereomers. Processes for isolating the individual diastereomers are described in the prior art (c.f. DE-OS-27 06 413 and U.S. Pat. No. 5,063,224).
For the purposes of the description, cefuroximaxetil preferably comprises the pharmaceutically usable mixture of the diastereomers, as is for example defined in USP 23, pages 315/316. The two diastereomers are here present in an approx. 1:1 ratio. According to USP 23, a sample of the mixture of diastereomers is chromatographed. A peak rA then corresponds to the A isomer and a peak rB to the B isomer. According to USP 23, page 315, right hand column, the ratio of the diastereomers is then determined using the formula rA/(rA+rB). This ratio must be between 0.48 and 0.55.
The production of dosage forms which are suitable for administering cefuroximaxetil is associated with various problems. On the one hand, these problems are attributable to the chemical and physical properties of the active ingredient, in particular to its bitter flavour and its comparatively poor solubility, which is largely pH-independent in an aqueous medium. On the other hand, however, the physical properties of conventional solid dosage forms, in particular their rate of disintegration under physiological conditions also play an important part.
One substantial problem which is directly attributable to the properties of the active ingredient itself is the only slight solubility of cefuroximaxetil in an aqueous medium. It is particularly unfavourable in this connection that this slight solubility prevails not only in gastric juice, but also at pH values which correspond to the physiological pH values of the small intestine. It is precisely in the small intestine that cefuroximaxetil should in principle be as rapidly available as possible, as this is largely where it is absorbed.
The bioavailability of cefuroximaxetil is inter alia a function of its solubility. USP 23 describes a test on page 316 for determining the bioavailability of cefuroximaxetil. To this end, the solubility of the active ingredient from a standardised tablet formulation is determined in methanol. Those products in which at least 60% of the active ingredient is dissolved in 15 minutes and at least 75% of the active ingredient is dissolved within 45 minutes are approved.
Various solid modifications of cefuroximaxetil are known in the prior art which are distinguished inter alia by different solubility.
The amorphous form of cefuroximaxetil is conventionally used for the production of oral dosage forms (c.f. DE-OS 34 27 828, EP-A 107 276 and U.S. Pat. No. 4,562,181). However, use of the amorphous form is problematic. It is accordingly known that at 37° C. amorphous cefuroximaxetil forms a sparingly soluble gel layer on the external surface of the particles when it comes into contact with water, so considerably delaying active ingredient release.
Apart from the amorphous form of cefuroximaxetil, various crystalline modifications of cefuroximaxetil are known. It has been reported that these crystalline modifications have a lesser tendency to form a gel than the amorphous form. However, in comparison with the amorphous form, hitherto known crystalline modifications exhibit lower solubility and thus also reduced bioavailability.
GB-A-15 71 683 accordingly discloses a modification which is hereinafter denoted the “α-modification”. An IR spectrum is disclosed in GB-A-21 45 409. The α-modification does not exhibit sufficient bioavailability for use as a pharmaceutical preparation; when tested according to USP 23, it does not achieve the specified minimum solubility. EP-A-757 991 discloses a modification which is hereinafter denoted the “β-modification”. However, when determined in accordance with the standard method according to USP 23 page 316, the solubility of the active ingredient only amounts to somewhat over 40% after 45 minutes. EP-A-937 727 discloses a modification which is hereinafter denoted the “γ-modification”. According to the disclosure of the document, 73.0% of the active ingredient are dissolved after 45 minutes (determined in accordance with the standard method according to USP 23, page 316). EP-A-937 727 furthermore discloses a hemihydrate which consists to an extent of approx. 95% of the R isomer.
Apart from its slight solubility, the bitter flavour of cefuroximaxetil also plays a part when formulating oral dosage forms.
Cefuroximaxetil is accordingly conventionally marketed in the form of film coated tablets (Elobact® and Zinnat®), which according to the manufacturers' instructions should not be crushed or chewed due to the bitter flavour of cefuroximaxetil. Other dosage forms are thus recommended for children below 5 years of age. Cefuroximaxetil is, for example, also marketed as a powder for suspension, the active ingredient being provided as a dry granular product. Shortly before the preparation is first taken, water is added to produce a suspension which can be stored in a refrigerator (+2° C. to +8° C.) for 10 days. Currently marketed powders for suspension contain a granular product of amorphous cefuroximaxetil, which is coated with stearic acid in order to mask the bitter flavour of the active ingredient (c.f. DE-OS-38 16 464). Despite the coating, this formulation still has an unpleasant, bitter flavour and so does not always meet with unreserved acceptance from children. The flavour even gets worse during storage of the suspension, as the coating softens over time. Furthermore, the bioavailability of cefuroximaxetil from this dosage form is approx. 30% lower than from comparable dosage forms with uncoated particles.
Apart from these difficulties due to the active ingredient, problems sometimes also occur which are determined not only by the active ingredient, but also by the dosage form.
Thus, even when the comparatively readily soluble amorphous cefuroximaxetil is used, in order to ensure sufficient bioavailability it is necessary for the dosage form, for example a film coated tablet, to disintegrate virtually instantaneously on contact with intestinal juice, such that the active ingredient particles may disperse and release the active ingredient rapidly without any appreciable gelation occurring. For this purpose, particles with a small diameter and large specific surface area are conventionally used for the production of film coated tablets.
The twice daily administration of cefuroximaxetil which is in principle desired entails a comparatively high active ingredient loading of the dosage forms. As is known, an elevated active ingredient loading may in particular be achieved with extruded pellets, which moreover comprise the desired smooth, preferably spherical form. A disadvantage of at these dosage forms is, however, that they usually have a very compact structure, which is primarily attributable to auxiliary substances such as microcrystalline cellulose (MCC). Due to their compact structure, these dosage forms do not disintegrate in an aqueous medium or at most disintegrate only very slowly, which may result in unwanted, greatly delayed release of cefuroximaxetil.
As a result, it is possible that release will occur to a considerable extent only in a lower portion of the intestine, so preventing adequate bioavailability of the active ingredient.
This low dissolution rate of the dosage form and the associated delayed release of the cefuroximaxetil is in particular observed when known spheronising agents, such as microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose are used, which, while indeed giving rise to pellets of the desired shape and with a narrow particle size distribution, result in delayed release of the active ingredient.
This is in particular observed in extruded pellets which have been produced with the assistance of the stated spheronising agents, once an existing coating, which may be resistant to saliva and/or gastric juice and also has a flavour neutralisation function, has dissolved. After the pH-dependent dissolution of the coating in the small intestine, such pellets disintegrate only very slowly, even in the presence of disintegrants and surfactants, so delaying the release of the cefuroximaxetil and limiting bioavailability.
Apart from the in any event comparatively poor disintegration characteristics of such pellets, an additional complicating factor with cefuroximaxetil is that, when the amorphous form of the active ingredient is used, release is complicated by gelation and, when known crystalline modifications are used, release is reduced as a result of their lower solubility. The bioavailability of the active ingredient from such pellets is not satisfactory; pellets are, for example, known which release only 20-30% of the active ingredient after 60 min.